Drug tolerance
Drug tolerance or physiological tolerance occurs when a subject's reaction to a drug (such as a painkiller or intoxicant) decreases so that larger doses are required to achieve the same effect. In addicted patients, the resulting pattern of uncontrolled escalating doses may lead to drug overdose. Tolerance may be related to the familiarity of "drug onset cues". The body is conditioned to respond to environmental cues such as the sight of a needle, and actually produces the beginnings of physiological responses before the drug is introduced. If there is no actual drug that follows, or if the dose is too small to produce the expected effect, it can trigger intense cravings in the addict. This may explain why "just one drink", or even the sight or presence of familiar alcohol cues, can cause a relapse in a recovering alcoholic. Tachyphylaxis Tachyphylaxis is a sudden onset drug tolerance which is not dose dependent. Mechanisms Pharmacokinetic tolerance Pharmacokinetic tolerance (dispositional tolerance) occurs because of a decreased quantity of the substance reaching the site it affects. This may be caused by an increase in induction of the enzymes required for degradation of the drug e.g. CYP450 enzymes. This is most commonly seen with substances such as ethanol, barbiturates, benzodiazapines and opiates. Pharmacodynamic tolerance Pharmacodynamic tolerance (reduced responsiveness) is the response to the substance is decreased by cellular mechanisms. This may be caused by a down regulation of receptor numbers. Tolerance is a reduced response to repeated administration of the same dose or increase in the dose are required to produce the same magnitude of response. Morphine as an example Tolerance to the analgesic effects of morphine is fairly rapid. There are several hypotheses about how tolerance develops, including opioid receptor phosphorylation (which would change the receptor conformation), functional decoupling of receptors from G-proteins (leading to receptor desensitization), mu-opioid receptor internalization and/or receptor down-regulation (reducing the number of available receptors for morphine to act on), and upregulation of the cAMP pathway (a counterregulatory mechanism to opioid effects) (For a review of these processes, see Koch and Hollt. ) CCK might mediate some counter-regulatory pathways responsible for opioid tolerance. CCK-antagonist drugs, specifically proglumide, have been shown to slow the development of tolerance to morphine or any other kind of drug, including alcohol. Significant involvement of the intracellular beta-arrestin-2 protein expression in the agonist-mediated desensitization of G protein-coupled receptors, such as the μ-opioid receptor (MOR), has been elucidated. It was reported that VTA dopamine neurons in rats remain increased for at least 3 days after a single morphine exposure. Within this limited window of time, the VTA dopamine neurons failed to respond to additional morphine challenge. Indicating a transient morphine tolerance in VTA DA neuron activity in rats was developed with a single dose of morphine treatment. It further demonstrated that this acute morphine tolerance was associated with impairment of opiate receptor-G protein coupling, indicating that down regulation of G-protein activation may contribute to acute morphine tolerance. See also *Conditioned drug tolerance *Contingent drug tolerance *[[Cross-tolerance *Desensitization *Drug resistance *Drug sensitivity *Mithridatization *Multidrug resistance *Physical dependence *Physiological tolerance *Reverse tolerance *Side effects (drugs) ---- In a different context, drug tolerance can refer to the lenient policies of a government or organization toward drugs that are considered illegal in other areas. For example, the distribution of marijuana has been legal in the Netherlands since the early 1970s, and the state of California continues to test the legality of its medical marijuana laws. Drug intolerance is another social issue. Many law enforcement and civic agencies (such as schools and scouting groups) advocate a zero tolerance policy towards drugs, meaning that any infraction of existing laws and regulations will be punished, no matter how small. Category:Pharmacodynamics